VEGF is a potent angiogenic and vascular permeability enhancing factor. VEGF may contribute to osteoarthritis (“OA”) pain and cartilage and bone structural changes by: 1) enhancing synovial inflammation, effusion, and angiogenesis, 2) promoting blood vessel invasion into cartilage, 3) contributing to bone marrow edema, 4) promoting local re-initiation of endochondral bone formation, resulting in tidemark duplication, bone sclerosis, chondrocyte hypertrophy, and cartilage thinning. It is likely therefore that blocking VEGF signaling is of benefit to relieve OA pain and/or to protect joint structure. It is known that VEGF is upregulated in human and animal models of OA and can be restored to normal levels in vivo by intra-articular treatment with a known analgesic agent. Recent findings also indicated that VEGF/KDR signaling may be up-regulated in OA, and cartilage and synovium are among the sources for VEGF over-expression under pathological conditions. Additionally, it was demonstrated that increasing VEGF expression by overexpressing its upstream regulator hypoxia inducible factor alpha (Hifla) in human synovial and chondrocyte cell cultures results in a substantial increase in cyclooxygenase-2 (COX-2) expression, which may be an indication of a painful stimulus. In animal models of OA, a significant correlation (r=0.437, p=0.008) was identified between levels of synovial fluid VEGF and prostaglandin E2 (PGE2), a neuronal sensitizing agent generated by cyclooxygenases, including COX-2, that has been used as a marker for pain in joints. Further, blocking VEGF in animal models of OA results in decreased synovial inflammation and hyperplasia, two factors correlated with OA pain in humans. Longer half lives of protein based inhibitors will be necessary to make this a viable therapeutic strategy. Multiple sustained release formulation efforts have been attempted, but all resulted in marked protein instability at specific locations in the protein sequence.
Accordingly, there exists a need for improved VEGF antagonist compositions so as to improve their stability, half lives, and other beneficial characteristics.